TGF-.beta.s play an important role in the regulation of cell proliferation and in tissue repair (for reviews see Roberts and Sporn, 1990; Massague, 1990). The TGF-.beta. family consists of three known isoforms. TGF-.beta.1, 2, and 3, that are structurally and functionally closely related to one another.
TGF-.beta. is a potent growth suppressor for epithelial, myeloid, and lymphoid cells. This together with the observation that many transformed cells are resistant to the growth suppressing effects of TGF-.beta. suggests that TGF-.beta. functions as a general homeostatic factor suppressing undesired cell proliferation. Consequently, abnormalities in TGF-.beta. function have been implicated in cellular transformation and malignancy (Masui et al., 1986; Shipley et al., 1986; Knabbe et al., 1987) and in a lymphoproliferative disorder seen in mice lacking a functioning TGF-.beta.1 gene (Shull et al., 1992; Kulkarni et al., 1993). A prominent feature among TGF-.beta. activities is the ability of this growth factor to enhance the deposition of extracellular matrix and stabilize such matrices (Sporn et al., 1983; Roberts et al., 1986). This is accomplished by increased production of extracellular matrix proteins (Balza et al., 1988; Ignotz and Massague, 1986; Bassols and Massague, 1988; Pearson et al., 1988) and their cellular receptors (Ignotz and Massague, 1987) as well as decreased proteolysis (Edwards et al., 1987; Laiho et al., 1987). These activities of TGF-.beta. are important in tissue repair.
TGF-.beta. induces its own production in many cells (Van Obberghen-Schilling et al., 1988; Kim et al., 1989), and sometimes this self-amplifying cascade can lead to excessive and destructive fibrous tissue formation (Border and Ruoslahti, 1992). The fact that TGF-.beta. is the driving force in many fibrotic disorders is suggested by elevated TGF-.beta. expression at the site of excessive matrix formation and by the ability of neutralizing anti-TGF-.beta. antibodies to hinder the development and progression of such disorders (Border and Ruoslahti, 1992). Considering the potency of TGF-.beta. in eliciting both beneficial and potentially harmful responses, an effective regulatory system balancing TGF-.beta. activity would be desirable.
One of the regulators of TGF-.beta. activity is the binding of TGF-.beta. to cell surface components other than signal transducing receptors and to extracellular matrices (Ruoslahti and Yamaguchi, 1991). A cell surface proteoglycan, betaglycan (also known as TGF-.beta. receptor type III), binds TGF-.beta. at the cell surface (Massague, 1992) apparently enhancing the binding of TGF-.beta. to one of the signal transducing receptors (Wang et al., 1991). A number of extracellular matrix (ECM) components have also been shown to bind TGF-.beta.. These include fibronectin (Fava and McClure, 1987), thrombospondin (Murphy-Ullrich et al., 1992), collagen type IV (Paralkar et al., 1991) and the core proteins of small interstitial glycans of the decorin family (Yamaguchi et al., 1990). The binding of TGF-.beta. to the decorin-type proteoglycans neutralizes the activity of the growth factor (Yamaguchi et al., 1990; Border et al., 1992). While betaglycan and the decorin-type proteoglycans bind TGF-.beta. through the core protein. TGF-.beta. can also bind to glycosaminoglycan chains of proteoglycans (McCaffrey et al., 1992). Immunohistochemical stainings have shown that, indeed, TGF-.beta. can be found in the extracellular matrix in vivo (Flanders et al., 1989; Heine et al., 1990; Silberstein et al., 1992), but the binding proteins involved in this localization are not known. This invention provides a purified TGF-.beta. binding protein.